Significance Insulin Dependent Diabetes Mellitus (IDDM) affects over a million young Americans and the social, human and medical costs of this chronic disease are enormous. The potential of developing a new strategy for successful islet transplantation to restore normal glucose metabolism to these patients is great. Objectives The present study was developed to test transplanting islets into the thymus of rhesus monkeys as a model for human islet transplantation. As this is also a xenotransplant model it could be used as a first test for pig islet donors, a solution to the limited number of available human organ donors. Results We started by creating a new strategy to render the monkeys diabetic and insulin-dependent. After 4 weeks, two insulin-dependent monkeys were transplanted intrathymically with human fetal islets (10,000 ICCs/kg). Our mouse studies indicate that it will take at least 3 months for these to mature and secrete insulin. Immunosuppression includes IV ATG induction followed by daily cyclosporine and a novel rapamycin called SDZ RAD. The animals are presently just 3 months post transplant, healthy and clinically stable. We have learned alot about insulin therapy, dosing, and complications of the cyclosporine and RAD as well as gained experience caring for immunosuppressed animals. Currently both are on lower doses of insulin than in the first month post transplant. At 2.5b months we measured C-peptide levels in fasting bloods of both monkeys, detecting C-peptide in one animal, again suggesting function of the islet transplant. At 3 months full IV GTTs will be done on both animals. Future Directions We are currently ready to make another two animals diabetic and transplant this time with adult human islets. If these experiments demonstrate islet development and function with intrathymic transplants, the next steps are to determine the requirements for longterm immunosuppression and whether tolerance is induced.